Advanced stage cancers are difficult to treat effectively, so it is important to detect them in their premalignant stages, such as dysplasia or carcinoma in situ. Currently, the most widely used method for early detection uses visual inspection through endoscopes, which relies upon the recognition of the gross architectural changes associated with dysplasia. Visual inspection is less effective in detecting the superficial lesions of flat dysplasia, such as ulcerative colitis and Barrett""s esophagus. In these cases, surveillance requires the selection of representative sites for biopsy and subsequent histological analysis. Only a very small fraction of a large surface, such as the colon, can be surveyed in this manner and small areas of dysplasia may go undetected. More efficient methods for detecting flat dysplasia would provide a significant means of reducing cancer morbidity, mortality, and costs.
A promising technique for detecting dysplasia during endoscopy involves illuminating the tissue with light of an appropriate wavelength and observing the resulting fluorescence. Tissue fluorescence occurs at longer wavelengths than the excitation illumination and is typically much weaker, so that spectroscopic techniques are generally required for its detection. Diagnostic methods which use fluorescence information can generally be divided into two groups. The first group of methods observes fluorescence from medications administered to the patient which have accumulated in tumor tissues. The second group of methods observes endogenous fluorescence or autofluorescence arising from substances natural to the tissue itself which change their relative concentrations when the tissue becomes dysplastic. Of the two general fluorescence methods, the first method, requiring a prior application of a drug, is the more invasive. The application of these drugs takes additional time and has the potential of causing adverse side effects. Methods based on autofluorescence detection are less invasive and more suited to endoscopy for screening purposes.
Normal colon tissue, for example, when illuminated with ultraviolet light at 370 nm, exhibits a broad, blue fluorescence with a peak at 450 nm, as shown in FIG. 1. This fluorescence is due to collagen, the primary protein of connective tissue, which is found within the thin mucosal layer and which is the dominant component of the submucosal layer. The fluorescence of dysplastic colon tissue, due to changes in its structure and chemistry, is typically xc2xd to ⅓ as intense given the same illumination. This reduction in visible blue-green autofluorescence, produced by ultraviolet to violet excitation light, has been identified as a primary indicator of dysplastic tissue. An increase in the relative fluorescence at 680 nm compared to 600 nm is a secondary indicator of dysplasia.
Diagnostic instruments which detect autofluorescence can be divided into two general groups. The first subdivision includes instruments which utilize fiberoptic probes to perform essentially point measurements on the tissue. The second subdivision includes instruments which produce detailed, two dimensional images. Point detection instruments have the advantage of providing more complete spectral information on the tissue, but are too slow for routine screening of large tissue areas and may miss small regions of dysplasia. Fluorescence imaging endoscopes are more appropriate for screening large tissue areas such as the colon.
Fluorescence imaging systems designed to sense concentrations of fluorescent markers that have been applied to the region of interest are optimized for the measurement of relatively high fluorescence levels, do not describe the additional instrumental features required to measure inherently weak autofluorescence. In particular, they do not describe a method for providing sufficient out-of-band filtering for the excitation illumination that would allow the effective measurement of autofluorescence, which typically is reduced in intensity, compared to the excitation intensity, by a factor of 1000 or more.
Fluorescence imaging endoscopes which are specifically designed to measure autofluorescence can be further divided into groups based on the excitation wavelength chosen and the method for quantifying the degree to which the autofluorescence is reduced. These design choices have a direct bearing on commercial considerations for the instrument since they affect, for example, the number of imaging devices required, the opto-mechanical complexity of the instrument, and the handling characteristics of the instrument in actual use.
Existing fluorescence imaging endoscope systems use visible blue light near 440 nm for the excitation wavelength, resulting in fluorescence peaks around 500 nm. These instruments use Helium-Cadmium lasers at 442 nm as a bright, easily controlled source for the excitation light. The high cost of Helium-Cadmium lasers makes them impractical as sources for commercial instruments.
Multiple cameras and mechanically switched optical components and/or filters require the use of endoscopes based on coherent imaging fiber bundles, so that the cameras and filters can be located at the proximal end of the endoscope where there is room for them. The coherent fiber imaging bundles introduce significant light losses and do not provide as sharp an image as those now available with video endoscopes.
The present invention relates to imaging endoscopes and in particular to an endoscope system and method for imaging autofluorescence from epithelial tissue to highlight regions of dysplasia. The system for detecting dysplastic tissue uses the autofluorescence of mucosal tissue such as that found in the colon, the esophagus, the oral cavity, the cervix and the lung. The fluorescence imaging apparatus for an endoscope of the present invention utilizes a selected range of excitation light wavelengths and a fluorescence normalization method. These choices provide for an improved endoscope which requires one, non-intensified, imaging detector at the distal tip of a video endoscope for both white light imaging and fluorescence imaging. The imaging detector can be a pixellated integrated circuit device such as a CMOS imaging device, charge coupled device (CCD) or other small two dimensional imaging sensors that can detect in the visible and infrared ranges.
The system of the present invention has the ability to switch back and forth between white light and fluorescence visualization methods electronically, requiring no moving parts within the endoscope itself. The elimination of cameras and imaging optics at the proximal end of the endoscope significantly improves its handling characteristics. A computer-based imaging system allows quantitative images of the tissue to be displayed, at refresh rates of up to 10 Hz or higher, for example. A preferred embodiment uses easily seen, false-color overlays which indicate the likely areas of tissue dysplasia. By xe2x80x9cfalse colorxe2x80x9d we mean that a color value is assigned to a particular level of fluorescence intensity for each pixel. A data processing system can be programmed to provide a color system suitable for imaging a given type of tissue condition. The system can be used either with color wheel (e.g., using a monochrome CCD) video endoscopes or with color imaging sensor endoscopes.
In a preferred embodiment, near ultraviolet light is chosen as the excitation wavelength, as described in Wang, et al., U.S. Provisional Application No. 60/072,455, Jan. 26, 1998. This choice in the range of 300-420 nm reduces or eliminates the need for additional filters between the tissue and the imaging detector due to the fact that standard, electronic imaging sensors, as used in video endoscopes, are insensitive to the excitation light. Visible red light, to which the imaging detector is very sensitive, is chosen to illuminate the tissue for the purpose of acquiring a reference image. This reference light is passed through the same optical guide as the excitation light, and illuminates the tissue with the same normalized spatial distribution and angular distribution as the excitation light. By correlating the spatial intensity and angular distribution of light used for the reflected image and the light for the fluorescence image, a more accurate and diagnostically useful imaging system is provided. This system of the present invention allows the reference image to be used to normalize the fluorescence image so that local reductions in fluorescence intensity can be accurately quantified. In another preferred embodiment, using color wheel (monochrome CCD) video endoscopes, the reference light and excitation light are applied sequentially. In another preferred embodiment, using color CCD video endoscopes, the fluorescence excitation light and reference light are applied simultaneously.